Protein Phosphorylation States in Drug Addiction

描述(由申请人提供)： 从药物滥用到成瘾状态的转变以自我给药过程中药物摄入量的上升为特征，戒断渴望显著增加。服药和寻药行为均受伏隔核(NAC)多巴胺D1D2受体的不同调控。药物诱导的cAMP/PKA信号上调可能通过不同地改变NAC中的多巴胺受体反应性而导致疾病的升级和复发。为了研究这一假说，研究将测量慢性可卡因、海洛因和乙醇自身给药所产生的体内NAC cAMP依赖的蛋白磷酸化的变化。此外，研究还将测量慢性服用可卡因后，对d1和d2受体调节cAMP依赖的蛋白磷酸化的敏感性的变化。NAC核心和外壳亚区cAMP依赖蛋白磷酸化的变化将与个体自我给药升级和戒断时复发为寻求可卡因的倾向进行比较。在体内，磷蛋白测量将包括AMPA和NMDA受体的pGluR1和pNR1亚单位，pDARPP-32，pCREB和PD1受体，使用一种新的位点特异性抗体。这些研究旨在了解毒品和酒精成瘾的分子机制，并可能确定治疗干预的目标。

DESCRIPTION (provided by applicant): The transition from drug abuse to the addicted state is characterized by the escalation of drug intake during self-administration, and markedly increased craving in withdrawal. Both drug-taking and drug-seeking behaviors are differentially regulated by D1 and D2 dopamine receptors in the nucleus accumbens (NAc). Drug-induced up-regulation of cAMP/PKA signaling may contribute to escalation and relapse, possibly by differentially altering dopamine receptor-responsiveness in the NAc. To investigate this hypothesis, studies will measure changes in NAc cAMP-dependent protein phosphorylation in vivo produced by chronic cocaine, heroin, and ethanol self-administration. Additionally, studies will measure alterations in sensitivity to D1 and D2 receptor-regulation of cAMP-dependent protein phosphorylation after chronic cocaine self-administration. Changes in cAMP-dependent protein phosphorylation in both core and shell subregions of NAc will be compared to individual propensities for escalating cocaine self-administration and relapse to cocaine seeking in withdrawal. In vivo phosphoprotein measures will include pGluR1 and pNR1 subunits of AMPA and NMDA receptors, pDARPP-32, pCREB, and pD1 receptor using a novel site-specific antibody. These studies are aimed at understanding molecular mechanisms that underlie drug and alcohol addiction, and may identify targets for therapeutic intervention.